Program Director/Principal Investigator (Last, First, Middle): PI: Alexey G. Ryazanov, Ph.D. Abstract The TOR pathway plays an important role in aging. It has been demonstrated that treatment with rapamycin leads to prolongation of life span in diverse organisms. One of the components of TOR pathway is eEF2 kinase (eEF2K) which regulates the global rate of protein synthesis through phosphorylation of elongation factor 2 (eEF2). Activation of TOR results in the inhibition of eEF2K as a part of the mechanism that increases the rate of protein synthesis. Recently, we generated mice with knockout of eEF2K and found that its inactivation protects stem cells from apoptosis and retards aging. Thus, there exists a paradox: on one hand inhibition of TOR slows down aging, on the other hand inhibition of TOR may accelerate aging through activation of eEF2K. Therefore, the inhibition of TOR by rapamycin results in two opposite signals: inhibition of the TOR pathway slows down aging and at the same time activates eEF2K, which may counteract the anti- aging effect of rapamycin. Thus, we hypothesize that simultaneous inhibition of TOR and eEF2K increases the effect of TOR inhibition on aging. We will test this hypothesis by determining whether inactivation of eEF2K can synergize with rapamycin in producing an anti-aging effect. PHS 398/2590 (Rev. 06/09) Page 1 Continuation Format Page